6-gem-difluoro steroids



United States Patent 3,546,215 6-GEM-DHFLUORO STEROIDS John H. Fried, Palo Alto, Calif., assignor to Syntex Corporation, Panama, Panama, a corporation of Panama N0 Drawing. Continuation-impart of application Ser. No.

676,060, Oct. 18, 1967. This application Sept. 30, 1968,

Ser. No. 763,918

Int. Cl. C07c 173/00 US. Cl. 260-23955 23 Claims ABSTRACT OF THE DISCLOSURE 6it,6B-difluoropregn-4-en-3-ones (substituted at C-ll with hydroxy or chloro, at C-2 1 with hydroxy, fluoro, chloro or the hydroxy esters thereof, optionally substituted at (1-9 with chloro or fluoro, at Cl6 with methyl, at 0-17 with hydroxy or the esters thereof, optionally, Cl6 and C17 are bridged by a cyclic acetal or ketal, optionally there is a double bond between C1,2) exhibit antiinfiammatory and glucocorticoid activity.

This application is a continuation-in-part of my copend ing application No. 676,060, filed Oct. 18, 1967, now abandoned.

The present invention relates to novel gem-difluoro steroid derivatives and to novel processes for the preparation thereof.

More particularly, the present invention relates to the novel 6a,6(3-difluoro steroids of the following formula:

wherein:

Where each of R and R is, independently of each other, hydrogen, lower alkyl, halogenated lower alkyl, monocyclic cycloalkyl, monocyclic cycloalkyl lower alkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic, or monocyclic heterocyclic lower alkyl; or R and R taken together with the carbon atom to which they are joined are monocyclic cycloalkylidene or monocyclic heterocyclic ylidene;

R' is hydroxy or chloro;

X is hydrogen, fluoro or chloro, provided that each of R and X is chloro when R is chloro; and

Z is a carbon-carbon single bond or a carbon-carbon double bond.

The wavy line at the Cl6 position indicates that the R substituent can be either in the aor fl-configuration.

Included within the present invention are 6-gem-difluoro steroids optionally substituted at the C9a position with fluoro or chloro; at the C-llfl position with hydroxy or chloro, provided that each of the C9oz and C-1l,6 positions are substituted with chloro only when both positions are simultaneously substituted with chloro; at the 0-160: or Cl6fi positions with methyl; at the C17oc position with hydroxy or an ester thereof; or at the C-2l position with fluoro, chloro, hydroxy or an ester thereof. The present novel 6-gem-difiuoro steroids are also optionally substituted with an acetal or ketal group bridging the l6a,17apositions.

The novel 6-ge1n-difluoro steroids of the present invention are valuable medicinal steroids possessing antiinflammatory and glucocorticoid activity. Accordingly, the present compounds are useful in the treatment of allergic diseases, collagen diseases, skin diseases, and the like. These novel steroids are administered via conventional pharmaceutical routes, such as orally, parenterally, topically, and the like.

The present compounds are administered in the usual pharmaceutically acceptable forms. For example, the present compounds are administered orally as solids in the form of pills, tablets, powders (free or encapsulated), and the like; or as liquids in the form of solutions, suspensions, syrups, and the like; the present compounds are usually administered parenterally as liquids in suspensions or solutions. The dosage for oral or parenteral administration is from about 0.001 mg. to about 1 mg. per kilogram of body weight per day. Topically, the present compounds are administered as powders, creams, ointments, solutions, suspensions, aerosoles, foams, and the like, containing about 0.001% to about 1% of the steroid, with the remainder being a pharmaceutically-acceptable inert vehicle or combinations of inert vehicles.

Orally, parenterally and topically, the present novel 6- gem-difluoro steroids are administered alone or in combination with one or more pharmaceutically-accepted therapeutic agents, such as antibiotics.

The term lower alkyl denotes a group comprising a straight or branch chain aliphatic hydrocarbon of from 1 to 6 carbon atoms. Typical lower alkyl groups include methyl, ethyl, isopropyl, butyl, hexyl, and the like. The term halogenated lower alkyl denotes a lower alkyl substituted with one or more halo atoms, preferably fluoro or chloro.

The term monocyclic cycloalkyl denotes a group comprising a cyclic hydrocarbon of 5 to 6 carbon atoms, i.e. cyclopentyl and cyclohexyl. The term monocyclic cycloalkyl lower alkyl denotes a lower alkyl group substituted with one cycloalkyl substituent.

The term monocyclic aryl denotes a phenyl group optionally substituted with 1 to 3 lower alkyl, hydroxy, fluoro, chloro or lower alkyloxy groups.

The terms monocyclic heterocyclic and monocyclic heterocyclic ylidene denote ring molecules of 5 to 6 carbon atoms containing 1 or 2 oxygen, nitrogen or sulfur atoms in the ring. Typical monocyclic heterocyclics include furan, morpholine, pyrrolidine, and the like. Typical monocyclic heterocyclic ylidenes include tetrahydrofuranylidene, pyridylidene, l-thia-1-oXide-4,4-cycloheXylldone and the like.

The terms monocyclic aryl lower alkyl and monocyclic heterocyclic lower alkyl denote lower alkyl of from 1 to 6 carbon atoms substituted with a monocyclic aryl or monocyclic heterocyclic group.

The term conventional hydrolyzable ester as used herein denotes those hydrolyzable ester groups conventionally employed in the steroid art, preferably those derived from hydrocarbon carboxylic acids or phosphoric acids and their salts. The term hydrocarbon carboxylic acid defines both substituted and unsubstituted hydrocarbon carboxylic acids. These acids can be completely saturated or possess varying degrees of unsaturation (including aromatic), can be of straight chain, branched chain or cyclic structure, and preferably contain from 1 to 12 carbon atoms. In addition, they can be substituted by functional groups, for example, hydroxy, alkoxy containing up to 6 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino, halogeno, and the like, attached to the hydrocarbon backbone chain. Typical conventional hydrolyzable esters thus included within the scope of the term and the instant invention are formate, acetate, propionate, butyrate, valerate, caproate, enanthate, caprylate, pelargonate, acrylate, undecenoate, phenoxyacetate, benzoate, phenylacetate, diphenylacetate, diethylacetate, trimethylacetate, t-butylacetate, trimethylhexanoate, methylneopentylacetate, cyclohexylacetate, cyclopentylpropionate, adamantoate, glycolate, methoxyacetate, hemisuccinate, hemiadipate, hemi-{ifi-dimethylglutarate, acetoxyacetate, 2 chloro 4 nitrobenzoate, aminoacetate, diethylaminoacetate, piperidinoacetate, fl-chloropropionate, trichloroacetate, fl-chlorobutyrate, dihydrogen phosphate, dibenzyl phosphate, benzyl hydrogen phosphate, sodium benzyl phosphate, cyclohexylammonium benzylphosphate, sodium phenyl phosphate, sodium ethyl phosphate, di-p-nitrobenzyl phosphate, sodium o-methoxyphenyl phosphate, cyclohexylammonium p-cyanobenzyl phosphate, sodium phenacyl phosphate, benzyl o-carbomethoxyphenyl phosphate, and the like.

The novel gem-difluoro compounds of the present invention are prepared from the corresponding 6-fluoro compounds. The novel process of the present invention can be illustrated by the following reaction sequence:

R R R and X are as defined hereinbefore;

R is hydrogen, hydroxy or chloro;

R is lower alkyl, preferably methyl or ethyl; and the wavy line at the -16 position indicates that the R substituent can be the 04- or B-configuration.

pared from the corresponding compounds of Formula III by the novel process of the present invention. Third step, the novel A -6-gem-difiuoro steroids, the compounds of Formula V, are in turn prepared from the corresponding novel compounds of Formula IV.

When R is hydrogen, a fourth step is required; the introduction of an llB-hydroxy group or an llfl-chloro group onto the compounds of Formulas IV and V to finish the llB-hydroxy compounds and the llfl-chloro compounds of Formula I.

The compounds of Formula III, the 3-enol ethers of the 6-fluoro starting steroids of Formula II, are prepared from the compounds of Formula II by conventional techniques known to the art. For example, the compounds of Formula II are treated with an alkyl orthoformate, preferably methyl orthoformate or ethylorthoformate, in the presence of an acid catalyst, such as sulfuric acid, p-toluenesulfonic acid, and the like, in an inert non-aqueous, preferably anhydrous, organic solvent to afford the compounds of Formula III.

The compounds of Formula 1 11 are then isolated by conventional techniques; for example, the reaction mixture is neutralized and water is added to solidify the enol ether derivatives. The solid is then collected by filtration.

The compounds of Formula III are then treated with perchloryl fluoride in an inert, non-aqueous, preferably anhydrous aprotic organic solvent, as for example, a N,N- dialkyl hydrocarbon carboxylic amide, such as dimethylformamide, dimethylacetamide, and the like, to furnish the novel compounds of Formula IV. The reaction is conducted at temperatures in the range of from about 0 C. to about C., conveniently at room temperature. At least a molar equivalent of perchloryl fluoride is used per molar equivalent of the compound of Formula III, and generally two or more molar equivalents of perchloryl fluoride are utilized.

The novel 6gem-difluoro steroids, the compounds of Formula IV, are isolated by conventional techniques. For example, the reaction mixture is cautiously neutralized with an aqueous basic solution and the novel product is crystallized by the addition of water. The solid product is collected by filtration. The product can then be purified by dissolving in an inert organic solvent, immiscible with 'water, as for example, a halogenated hydrocarbon, such as methylchloride, or a water-immiscible ether, such as diethylether; washing with water to neutrality, drying and evaporating to dryness. The product can be further purified by recrystallization, chromatography, and the like. The novel compounds of Formula IV where R is bydroxy or chloro, are the novel 6-gem-difluoro steroids of Formula I wherein Z is a carbon-carbon single bond.

The '6-fluoro group of the 6-fluoro starting steroid of Formula II is either in the alpha or beta configuration. The present process is operable with starting steroids possessing either the 612- or 6/3-fluoro configuration.

The A unsaturation, the Cl,2 double bond, is introduced into the novel compounds of Formula IV by conventional techniques to furnish the novel A compounds of Formula V. For example, the novel compounds of Formula IV can be refluxed with selenium dioxide in the presence of t-butynol and pyridine, or refluxed. with selenium dioxide and chlorobenzene, or refluxed with 2,3-dichloro-5,6-dicyano-1,4-benzoquiuone to afford the compounds of Formula V. The compounds of Formula V, wherein R is hydroxy or chloro, are the novel 6-gem difluoro steroids of Formula I, wherein Z is a carboncarbon double bond.

The compounds of Formula V are isolated by conven tional techniques. For example, the reaction mixture may be evaporated to dryness, the residue taken up in an inert organic solvent immiscible with water, washed to neutrality, dried and evaporated to dryness. The compounds can be further purified by recrystallization, chromatography, and the like.

In the situation where the compounds of Formulas 1V and V are unsubstituted at the -115 position, the 11phydroxy group is introduced by incubating such compounds with excised adrenal glands or extracts thereof, or incubating with llfi-hydroxylating micro-organisms such as Cunninghamella bainieri or Curvularia lunata, in an appropriate nutrient media.

In the preferred embodiment of the above described process, R is fiuoro, chloro or a conventional hydrolyzable ester.

In the preferred embodiment of the present invention, 6-fluoro-9a,11fl-dichloro starting steroids of Formula II are employed to prepare 6-gem-dii'luoro-9a,1lfi-dichloro steroids.

In the preferred embodiment of the present invention, the 17u-acyloxy-21-hydroXy configuration in the compounds of Formula I is introduced after the introduction of the 6-gem-difluoro moiety and the A unsaturation. Such configuration can be introduced by hydrolyzing the corresponding 170:,21 (1' methoxy) l',1' alkylidenedioxy 6-gem-difiuoro steroid derivatives with a mineral acid in a lower alkanol to afford the corresponding 17ccacyloxy-Zl-hydroxy 6-gem-difluoro steroid of Formulas IV or V. The 17a,21 (1' methoxy)l',1 alkylidenedioxy G-gem-difluoro steroid derivatives are prepared by treating 17a,21-dihydroXy o-gem-difluoro steroid derivatives with the corresponding trimethyl alkylidynetrioxy in the presence of an acid catalyst.

The 6-fiuoro starting steroids employed in the present process and used to prepare the present novel 6-gem-difluoro steroids are described in the literature and in United States and foreign patents. For example, see U.S. Pats. 2,983,737, 2,983,739, 3,053,838, 3,057,858, 3,124,- 251, 3,126,375, 3,201,391 and 3,248,389.

In addition, the 6-fluoro starting steroids can be prepared by conventional techniques well-known to the art from steroids of the following formula:

CHzOH {i=0 W O wherein R is hydrogen or hydroxy.

For example, the 6-fiuoro group is introduced by treating a 3-alkoxy-A steroid with perchloryl fluoride in dimethylformamide. The 9zx-fill01'0 or -chloro group is introduced by treating a 96,11,8-oxido steroid with hydrogen fiuoride or hydrogen chloride respectively in an inert, nonaqueous, preferably anhydrous, solvent or mixture of such solvents. The 95,11,8-oxido steroid is prepared from the corresponding A9901) steroid (which is prepared by treating the corresponding 11-hydroxy-A steroid with methane sulfonyl chloride in dimethylformamide in the presence of pyridine) by treating the latter with N-bromo acetamide and perchloric acid in dioxane or tetrahydrofuran, and then refluxing the resulting 9-bromo-11-hydroxy steroid with potassium acetate in acetone. The 904,11fi-dichloro groups are introduced by treating the corresponding A901) steroid with chlorine gas in chloroform.

The 16-methyl group is introduced by treating the corresponding ZO-keto-A steroid with methyl magnesium bromide in the presence of cuprous chloride in an ether such as tetrahydrofuran. The 20-keto-A steroid is prepared by preparing the 3,20-bis-semicarbazone of a 3,20- diketo-17a-hydroxy steroid, treating it with glacial acetic acid and acetic anhydride and then allowing the resulting product to react with aqueous pyruvic acid.

The 17a-hydroxy group is introduced in conjunction with the 16-methy1 group 'by first treating the corresponding 16-methyl-A steroid (which is prepared by treating the corresponding A steroid with diazornethane and then heating the resulting product to C.) with hydrogen peroxide, in an aqueous basic media, then permitting the resulting 16,17-oxido-16-methyl steroid to react with hydrogen *brOmide in glacial acetic acid. The resulting 16, 17-bromohydrin is hydrogenated with the use of a palladium catalyst to afford the corresponding 16-methyl-17ahydroxy derivative.

The 16a,17a-dihydroxy groups are introduced by treating a A steroid derivative with potassium permanganate, acetone and acetic acid. The 1606,17oL-8C6t21l or ketal groups are introduced by treating the corresponding 16a, 17a-dihydroxy steroid in presence of perchloric acid with a lower alkanal, such as paraldehyde, propanal, and hexanal; halogenated lower alkanal, such as chloral hydrate trifluoroacetaldehyde hemiacetal and hapta fluorobutanal ethyl hemiacetal; a di(lower alkyl)ketone, such as acetone, diethylketone, dibutylketone, methylethylketone, and methylisobutylketone; a halogenated di(lower alkyl)ketone, such as 1,1,1-trifiuoroacetone; a cycloalkanone, such as cyclopentanone, cyclohexanone, cyclobutanone, and cyclodexanone; mono and dicycloalkyl ketone, such as cyclohexylmethyl ketone and dicyclopropyl ketone; a monocyclic aromatic aldehyde, such as benzaldehyde, halobenzaldehydes (e.g. p-chlorobenzaldehyde and p-fluorobenzaldehyde), lower alkoxy benzaldehydes (e.g. o-anisaldehyde), di(lower alkoxy)benzaldehydes (e.g. veratraldehyde), hydroxybenzaldehydes (e.g. salicylaldehyde), dihydroxybenzaldehydes (e.g. resorcylaldehyde), lower alkyl benzaldehydes (e.g. m-tolualdehyde and p-ethylbenzaldehyde), di(lower alkyl)benzaldehydes (e.g. o,p-dimethylbenzaldehyde), acylamidobenzaldehydes (e.g. N-acetylanthranilaldehyde), monocyclic aromatic lower alkanals, such as phenylacetaldehyde, a-phenylpropionaldehyde, p phenylpropionaldehyde, 'y phenylbutyraldehyde, and aromatically-substituted halo, lower alkoxy, hydroxy, lower alkyl, acylamido and derivatives thereof; monocyclic heterocyclic aldehydes, such as picolinaldehydes, furfural, thiophene carbonals and halo, lower alkoxy, hydroxy, and lower alkyl derivatives thereof; a monocyclic heterocyclic lower alkanal such as oxacyclopen-4-yl acetaldehyde; a monocyclic aromatic lower alkyl ketone, such as acetophenone, propiophenone, butyrophenone, valerophenone, isocaprophenone, halophenyl lower alkyl ketones (e.g. p-chloroacetophenoue, pfluoroacetophenone, p-chloropropiophenone and p-fluoro propiophenone), (lower alkoxy) phenyl lower alkyl ketones (e.g. p-anisyl methyl ketone), di(lower alkoxy) phenyl lower alkyl ketones, hydroxyphenyl lower alkyl ketones, dihydroxyphenyl lower alkyl ketones (e.g. resacetophenone), (lower alkyDphenyl lower alkyl ketones (e.g. methyl p-tolyl ketone), di(lower alkyl)pheny1 lower alkyl ketones (o,p-xyly1 methyl ketone), and acylamidophenyl lower alkyl ketones (e.g. acetylanilines), benzophenone, and mono or his substituted fiuoro or chloro, lower alkoxy, hydroxy, lower alkyl, acylamido derivatives thereof; a monocyclic aromatic lower alkanone, such a 1- phenyl-3-butanone and l-phenyl-4-pentanone, and aromatically substituted derivatives thereof; monocyclic heterocyclic ketones, such as 2-acety1furan, 2-benzoyl furan, and Z-acetylthiophene; monocyclic heterocyclic lower alkanones; and monocyclic heterocyclic ketones, such as alloxan.

The 21 chloro group is introduced by treating a 21- hydroxy steroid derivative with a molar triphenyl phosphine in carbon tetrachloride, optionally in the presence of dimethylformamide or dimethylacetamide, at about room temperature.

The 21 fiuoro group is introduced by tosylating a 21- hydroxy steroid derivative with tolylsulfonyl chloride in pyridine, then refluxing th resulting 21-tolylsulfonate ester with sodium iodide in acetone to get the correspond ing 21-iodo steroid derivative; and lastly refluxing the latter with potassium fluoride in ethylene glycol.

The 21- and 1706-hYdI'OXY groups are etherified and esterified by conventional methods well-known to the art. For example, a 17a-hydroxy steroid is etherified by treating it with sodium hydride and then allowing it to react with an alkyl halide or the like. A 2l-hydroxy steroid is esterified by treating it with an acid anhydride in pyridine.

Where R is hydrogen in the derivatives of the compounds of Formula VI, the llfi-hydroxy group is intro duced by incubating the compounds with excised adrenal glands or extracts thereof, or by incubating with 11,8- hydroxylating micro-organisms such as Clmninghamella bainz'eri or Curvularza Luizaza in a nutrient media.

The novel process is not limited to the aforementioned 6-fluoro steroid derivative of the pregnane series, but rather, the novel process can be conducted on any 3- alkoxy-A -6-fluoro steroids to obtain the corresponding 60,6fl-dlfltl0l'0 steroids. Accordingly, 6-fluoro steroids of the androstane, estrane or pregnane series, and the like, can be employed. The reaction parameters described above are employed on all 6-fluoro starting steroids of any series.

The following examples are intended to further illustrate and typify the nature of this invention. These examples are presented solely for the purpose of exemplification, and they should not be construed as a limitation on the scope of this invention.

EXAMPLE 1 Part A.To a suspension of 1 g. of 6a-fiuoro-11fihydroxy-16a,l'ia-isopropylidenedioxy 21 acetoxypregn- 4-ene-3,20-dione in 7.5 ml. of anhydrous, peroxide-free dioxane are added 1.2 ml. of freshly distilled ethyl ortho formate and 0.8 g. of p-toluenesulfonic acid. The mixture is stirred at room temperature for minutes and then allowed to stand at room temperature for 30 minutes. There is then added 0.8 ml. of pyridine, followed by water until solidification occurs. This solid is collected by filtration, washed with water and air dried to yield 3- ethoxy-6ot-fluoro 115 hydroxy-16u,17u-isopropylidenedioxy-2l-acetoxypregna-3,5-dien-20-one, which is recrystallized from acetonezhexane.

Part B.A stream of perchloryl fluoride is passed through a solution of 1 g. of 3-ethoxy 6a-fluoro-llflhydroxy 16a,17u-isopropylidenedioxy-2l-acetoxypregna- 3,5-dien-20-one in ml. of dimethylformamide, cooled to 20 C. for 95 minutes. After being allowed to slowly attain a temperature of 25 C., the solution is poured into water and extracted with ethyl acetate. These extracts are washed wih saturated aqueous sodium bicarbonate solution and with water to neutrality, dried over sodium sulfate and evaporated to dryness to yield 6a,6fl-difluoro- 11 B-hydroxy 160:,170: isopropylidenedioxy-21-acetoxypregn 4 ene 3,20 dione, which is recrystallized from acetonezhexane.

Similarly, 60:,63 difiuoro 11,8 hydroxy-16a,17a-isopropylidenedioxy 21 acetoxypregn-4-ene-3,20-dione is obtained when 6B-fluoro-1lfl-hydroxy-16or,17a-isopropylidenedioxy-21-acetoxypregn-4-ene-3,ZO-dione is employed in the above processes of Example 1 as the 6-fiuoro starting steroid.

Part C.A mixture of 1 g. of 6a,6,8-difluoro-11B- hydroxy 16a,17a-isopropylidenedioxy2l-acetoxypregn- 4-ene-3,20-dione, ml. of t-butanol, 0.4 g. of recently sublimed selenium dioxide and 0.2 ml. of pyridine is refluxed under nitrogen for 48 hours, cooled and filtered through Celite diatomaceous earth. The filtrate is evaporated under reduced pressure and the residue dissolved in acetone. This solution is refluxed in the presence of charcoal for 1 hour, filtered through Celite diatoniaceous earth and evaporated. The residue is then chromatographed on neutral alumina to yield ,6B-difiii0i0-llflhydroxy 16a,17u-isopropylidenedioxy-Zl-acetoxypregna- 1,4-diene-3,20-dione.

By the method of the processes of Parts A and B are obtained.

EXAMPLE 2 The following compounds are prepared from the corresponding 6aand/or 6/3-fluoro steroids by employing the latter as starting materials in Part A of the process of Example 1, and subsequently employing the resulting 3- ethoxy-A steroids as starting materials in Part B of the process of Example 1:

6u,6p,21-trifluoro-9a, 1 1 B-dichloro-16u, 17 a-( 3,3-

hexylidenedioxy)pregn-4-ene-3,20-dione; and

6 a,6fi,2l-trifluoro-l 1/8-hydroxy-16a,17u-(1'-thia-4',4'-

cyclohexylidenedioxy dioxide) pregn-4-ene-3,20-dione.

By employing the above novel 6-gem-difluoro steroids as starting materials in Part C of the process of Example 1 or Part C of the process of Example 3, the corresponding A -6-gem-difluoro steroids are obtained.

EXAMPLE 3 Part A.T o a suspension of 1 g. of 60c,9ot-diflt101'0- 113,170 dihydroxy l6a-methyl-2l-chloropregn-4-ene 3,20-dione in 7.5 ml. of anhydrous, peroxide-free dioxane are added 1.2 ml. of freshly distilled ethyl orthoformate and 0.8 g. of p-toluenesulfonic acid. The mixture is stirred at room temperature for 15 minutes and allowed to stand at room temperature for 30 minutes. There is then added 0.8 ml. of pyridine, followed by water until solidification occurs. This solid is collected by filtration, washed with water and air-dried to yield 3-ethoxy-6,9a-difluoro- 113,170: dihydroxy-16a-methyl-2l-chloropregna-3 ,S-dien- 20-one, which is recrystallized from acetonezhexane.

Part B.A stream of perchloryl fluoride is passed through a solution of 1 g. of 3-ethoxy- 6ix,9u-difluoro- 1113,1741 dihydroxy 160: methyl-Zl-chloropregna-B',5- dien-20-one in 25 ml. of dimethylformamide, cooled to C., for 5 minutes. After being allowed to slowly attain a temperature of 20 C., the solution is poured into water and extracted with ethyl acetate. These extracts are washed with a saturated aqueous sodium bicarbonate solution and then with water to neutrality, dried over sodium sulfate and evaporated to dryness to yield 6ut,6fi,9atrifiuoro 115,170 dihydroxy 16a methyl-Zl-chloropregn-4ene-3,20-dione, which is recrystallized from acetone:hexane.

Part C.A mixture of 0.5 g. of 6u,6B,9a-trifluoro- 11,3,17a-dihydroxy-16a-methyl 21 chloropregn-4-ene- 3,2O-dione, ml. of dioxane and 0.35 g. of 2,3-dichloro- 5,6-dicyano-1,4-benzoquinone is refluxed for 10 hours. The mixture is then cooled, filtered and evaporated to dryness. The residue is dissolved in acetone and this solution is filtered through 10 g. of alumina and concentrated to yield 6a,6/3,9a-trifluoro-l lfi,l7a-dihydroxy-l6fl-rnethyl- 2l-chloropregna-1,4-diene-3,ZO-dione.

Similarly, the following novel A -6-gem-difiuoro steroids are prepared from the corresponding A -6uor 65- fluoro steroids:

By employing the above novel A -6-gem-fluoro steroids in the process of Part C the following novel A -6-gemfluoro steroids are respectively prepared:

60,6/3-difillOIO-l 113,l7a-dihydroxy-16u-methyl-2lacetoxypregna-l,4-diene-3,20-dione;

EXAMPLE 4 The following 6-gem-difiuoro steroids are prepared via the methods of Steps A and B of Example 3 from the corresponding 6-fiuoro steroids:

By employing the above 6-gem-difluoro-A steroids as starting materials in the process of Part C of Example 3, the corresponding G-gem-difluoro-A steroids are prepared.

EXAMPLE 5 A suspension of 1 g. of 6a,6B,9u-trifluoro-115,17ot-dihydroxy-Zl-acetoxypregna-1,4-diene-3,20-dione in 60 ml. of methanol is treated with a solution of 1 g. of potassium carbonate in 6 ml. of water. The mixture is heated at reflux for one hour, cooled in ice and diluted with water. The solid which forms is collected by filtration, washed with water and dried to yield 6a,6,B,9a-trifluoro ll/3,17a,21 trihydroxypregna-1,4-diene 3,20- dione, which is recrystallized from acetonezhexane.

Similarly, the other 21-acyloxy-6-gem-difiuoro steroids prepared in accordance with the processes of Examples 1 and 3, or named in Examples 1-4 can be hydrolyzed to afford the corresponding 2l-hydroxy compounds.

EXAMPLE 6 Part A.--To a mixture of 1 g. of 61x,6;3-difiuoro-91x, 1lfl-dichloro-l71x,21-dihydroxypregna 1,4 diene-3,20 dione and ml. of anhydrous peroxide free dioxane is added 4 g. of methyl ortho valerylate and 0.5 g. of ptoluenesulfonic acid. The mixture is heated at 100 C. for a period of 2 hours; then it is cooled and 1 ml. of pyridine is added, followed by the addition of 100 ml. of water. The resulting solid is collected by filtration, washed with water, and dried to yield 6a,6B-difiuoro-9u,11fl-dichloro l71 1,21-(1'-methoxy-1',l'-pentylidenedioxy)-pregna l,4-diene-3,20-dione, which is recrystallized from acetonezhexane.

Part B.A solution of 1.5 g. of 6a,6/3-difluoro-9o1,11;3- dichloro 1711,21 (1-methoxy-1,1-pentylidencdioxy) pregna 1,4 diene-3,20-dione and 40 ml. of methanol and 30 ml. of 2 N oxalic acid are heated at 40 C. for 10 minutes. The reaction mixture is evaporated under reduced pressure, and the resulting residue is crystallized from methanol to yield 6a,6B-difiuoro-9a,1lfi-dichloro- 171x-valeryloxy-2l-hydroxyprega-l,4-diene-3,20-dione.

Similarly, 6111,65 difiuoro-901,11fidichloro-l7o1-acet0xy- 21 hydroxypregna 1,4-diene-3,20-dione; 6a,6,8-difluoro- 91 1,11fi-dichloro 171x butyryloxy-Z1-hydroxypregna-1,4- dime-3,20 dione; and 601,6,8 difluoro-9o1,1l,3-dichloro- 171x-caproyl0xy 21 hydroxypregna-1,4 diene-3,20-dione are prepared by using methyl ortho acetate, methyl ortho butyrate and methyl ortho caproate in the above process.

EXAMPLE 7 A mixture of 1 g. of 6u,6,6,9a trifluoro-115,21-dihydroxy 1601,1701 isopropylidenedioxypregna 1,4-diene- 3,20-dione, 4 ml. of pyridine and 7 ml. of caproic anhydride is allowed to stand at room temperature for hours. The mixture is then poured into ice water and the solid which forms in collected by filtration, washed with water and dried to yield 61x,6fi,91 1-trifluoro-l1,8-hydroxy- 1601,1701 isopropylidenedioxy 21 caproyloxypregna- 1,4 diene-3,20-dione, which may be further purified through recrystallization from acctonezhexane.

EXAMPLE 8 Part A.To a suspension of 1 g. of Goa-fluOIO-l7aethynyl 17 8 hydroxyestr-4-en-3-one in 7.5 ml. of anhydrous, peroxide free dioxane added 1.2 ml. of freshly distilled ethyl orthoformate and 0.8 g. of p-toluenesulfonic acid. The mixture is stirred at room temperature for 15 minutes and then allowed to stand at room temperature for 30 minutes. There is then added 0.8 ml. of pyridine, followed by water until solidification occurs. This solid is collected by filtration, washed with water and air dried to yield 3 ethoxy 6oz fiuoro-lh-ethynylestra- 3,5-dien-17p3-ol, which is recrystallized from acetonezhexane.

Part B.A stream of perchloryl fluoride is passed through a solution of 1 g. of 3 ethoxy-6o1-fluoro-17a ethynylestra 3,5 dien 175-01 in 25 ml. of dimethylformamide, cooled to 20 C. for 95 minutes. After being allowed to slowly attain a temperature of C., the solution is poured into water and extracted with ethyl acetate. These extracts are washed with saturated aqueous sodium bicarbonate solution and with water to neutrality, dried over sodium sulfate and evaporated to dryness to yield 601,6;3 difiuoro 171x ethynyl-17,8-hydroxyestr-4- cn-3-one, which is recrystallized from acetonezhexane.

Similarly, 611,63 difiuoro 17a acetoxypregn-4-ene- 3,20 dione and 61x,6,8-difluor0l71x-ethynyl-17B-acetoxyandrost 4 en-3-one are prepared from 6111 fluoro-171zacetoxypregn 4 ene 3,20 dione and 6 fiuoro-17o1- ethynyl 17/3 acetoxyandrost 4 en-3-one respectively by the processes of Parts A and B of the above process.

What is claimed is: 1. The compounds of the formula:

CI-IzR wherein:

where each of R and R is, independently of each other, hydrogen, lower alkyl, halogenated lower alkyl, monocyclic cycloalkyl, monocyclic cycloalky lower alkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic, monocyclic heterocyclic lower alkyl; or R and R together with the carbon atom to which they are joined are monocyclic cycloalkylidene or monocyclic heterocyclic ylidene; R is hydroxy or chloro; X is hydrogen, fiuoro or chloro, provided that each of R and X is chloro when R is chloro; and Z is a carbon-carbon single bond or a carbon-carbon double bond. 2. The compounds according to claim 1: R is hydroxy, fluoro, chloro or acetoxy; R is hydrogen, hydroxy, acetoxy, or valeryloxy; R is hydrogen or methyl; R and R when taken together are the group O\ R4 :z; O/

where each of R and R is, independently of each other, methyl, ethyl, propyl or butyl; or R and R taken together with the carbon atom to which they are joined are cyclopentylidene, cyclohexylidene, 4',4' tetrahydropyranylidene, 4',4'-piperidylidene, N methyl-4',4-piperidylidene, N-ethyl,4,4 piperidylidene, l'-thia 4',4-cyclohexylidene, 1' thia 4',4' cyclohexylidene oxide 01' 1'-thia-4',4-cyclohexylidene dioxide; and

R and X are as defined in claim 1.

3. The compounds according to claim 2 which are 601,6 6 difiuoro 11,9,171 1,21 trihydroxy 16o1-methylpregna 1,4 diene-3,20-dione and the 21-acetate ester thereof.

4. The compound according to claim 2 which is 611,613,21 trifluoro 1113,1711 dihydroxy 161x-methylpregna-l,4-diene-3,20-dione.

5. The compound according to claim 2 which is 6111,66- difluoro 11fi,171 1-dihydroxy-161x-methyl-2l-chloropregnal,4-diene-3,20-dione.

6'. The compounds according to claim 2 which are 6a,6,8,91 1-trifluoro 1lfl,l7oc,.2l trihydroxy-l6a-mcthyl- 13 pregna-1,4-diene-3,20-dione and the 21-acetate ester thereof.

7. The compound according to claim 2 which is 60:, 6fi,9a,21-tetrafluoro 11fi,17a dihydroxy-l6a-methylpregna-l,4-diene-3,20-dione.

8. The compound according to claim 2 which is 60:, 66,90 trifiuoro 11,3,17m dihydroxy-16a-methyl-21- chloropregna-l,4-diene-3,20-dione.

9. The compounds according to claim 2 which are 6a,6B-difluoro 115,21 dihydroxy-16a,17a-isopropylidenedioxypregna-1,4-diene-3,20-dione, and the 21-acetate ester thereof.

10. The compound according to claim 2 which is Get, 613,21-trifluoro-1lfl-hydroxy 16a,17a isopropylidenedioxypregna-1,4-diene-3,20-dione.

11. The compound according to claim 2 which is 60:, 6fl-difiuoro-11B-hydroxy 16a,17a isopropylidenedioxy- 21-chloropregna-1,4-diene-3,20-dione.

12. The compounds according to claim 2 which are 6a,6,B,9a-lriflll0l'0 115,21 dihydroxy-la,17a-isopropylidenedioxypregna-1,4-diene 3,20 dione and the 21-acetate ester thereof.

13. The compound according to claim 2 which is 60:, 6,8,9a,21-tetrafluoro 11B hydroxy-l6u,l7a-isopropylidenedioxypregna-1,4-diene-3,20-dione.

14. The compound according to claim 2 which is 60c, 6 8,9a-trifiuoro-1lfl-hydroxy 16a,17a isopropylidenedioxy-Z1-chloropregna-1,4-diene-3,20-dione.

15. The compounds according to claim 2 which are 6a, 65 difiuoro 9u,11;3 dichloro-17a,21-dihydroxy-16amethylpregna 1,4 diene-3,20-dione and the 2l-acetate ester thereof.

16. The compound according to claim 2 which is 60:, 6,6,21-trifluoro 911,115 dichloro-lh-hydroxy-16a-methylpregna-1,4-diene-3,20-dione.

17. The compound according to claim 2 which is 6a, 6 8-difluoro 9a,lll3,2l trich1oro-17a-hydroxy-16a-methylpregna-1,4-diene-3,20-dione.

R is acetoxy or valeryloxy; R is methyl; and R R X and Z are as defined in claim 2.

22. The compounds according to claim 21 which are 6a,6B-difluoro 115,21 dihydroxy-17a-valeryloxy-16amethylpregna-1,4-diene 3,20 dione and the ZI-acetate ester thereof.

23. The compounds according to claim 21 which are 6u,6fl,9a-trifiuoro 115,21 dihydroxy-l7a-valeryloxy- 16a-methylpregna-1,4-diene-3,20dione and the 21-acetate ester thereof.

References Cited UNITED STATES PATENTS 3,264,332 8/1966 Gould et a1. 260-39745 3,282,969 11/1966 Boswell 260-397.3

OTHER REFERENCES Nakanishi et al.: J.A.C.S. vol. 81, pp. 5259-60.

HENRY A. FRENCH, Primary Examiner U.S. Cl. X.R. 

